Although adolescence is the most common period of onset of bipolar disorder and mania is the defining state of this illness, manic adolescents with bipolar disorder often undergo several unsuccessful medication trials prior to achieving mood stabilization, during which time illness progression occurs. Therefore, understanding the neurophysiologic effects of pharmacological interventions in these adolescents, will clarify the effects of anti-manic treatments on the neurodevelopment of bipolar disorder and may lead to the identification of neurobiological markers associated with treatment response, thereby facilitating rationale treatment assignment. Currently, such markers are lacking for bipolar disorder and are more difficult to detect later in the course of illness. Bipolar disorder is characterized by disruption of mood and attention. The anterior limbic network, which includes prefrontal regions (e.g., ventrolateral prefrontal cortex and anterior cingulate cortex), thalamus, amygdala, and striatum, appears to regulate these processes. Therefore, we hypothesize that the symptoms of bipolar disorder arise from dysfunction within this network. Indeed, neuroimaging studies suggest that abnormal activation and metabolism in prefrontal anterior limbic regions may underlie the neurophysiologic changes that produce the progressive emotional instability associated with bipolar disorder. Although it is unknown whether treatments for bipolar disorder interrupt these changes, this model provides potential targets to determine the neurobiological effects of medication and treatment response in bipolar adolescents. With these considerations, the overall goals of this proposal are to combine novel neuroimaging techniques with a systematic treatment study of early-course manic adolescents in order to 1) determine how neurophysiologic measures associated with mania change in response to treatment; 2) demonstrate that normalization of regional brain activation changes are associated with normalization of regional metabolite levels; and 3) identify neurometabolitic and neurofunctional markers that are associated with subsequent treatment-specific response. In order to accomplish these aims, we will randomize 120 first-hospitalization manic adolescents to double-blind treatment with lithium or quetiapine for 6 weeks, during which time we will perform symptom ratings, as well as fMRI and H-MRS scans. We will also recruit 60 healthy subjects to 1 assess normal variability in neurophysiologic measurements between time points and interpret the direction of the neurobiological changes in bipolar adolescents. Examining changes in these measures over the course of the study in each treatment group will determine whether effective pharmacological interventions interrupt the progression of the changes associated with mania and may identify treatment-specific markers of response. Ultimately, these findings may lead to targeted treatment development and assignment, as well as, early detection and intervention strategies, thereby improving illness outcome for bipolar adolescents. The overall goal of this R01 application is to conduct a study combining novel neuroimaging techniques with a systematic treatment study of early-course manic adolescents in order to clarify neurophysiologic effects and markers of treatment response. Despite the significant morbidity and mortality associated with adolescent-onset bipolar disorder, few studies have examined the neurobiological effects of anti-manic medications in this population. Findings of the proposed study will facilitate rationale treatment assignment and the development of potential early-intervention strategies and novel therapeutic agents; ultimately leading to improved outcomes of adolescents with bipolar disorder.